DESCRIPTION: (abstract verbatim) Oropharyngeal candidiasis (OPC) is a major problem in patients with AIDS, diabetes, and a number of other predisposing conditions. The predominant species, Candida albicans, may be found in small numbers in healthy persons but the numbers increase dramatically when OPC is found. The nature of host resistance to Candida is poorly understood in that it is not at all clear why the numbers of yeast remain low in healthy persons. The PI proposes that the interactions of C albicans with toll-like receptors play a role in the induction of protective defenses. In our preliminary experiments, the PI has found that C. albicans mannan, as well as lipopolysaccharide from Gram-negative bacteria, regulates several different TLRs in murine macrophages. The PI plans to analyze the kinetics of TLR gene expression after macrophage exposure to mannan. In addition to assaying mRNA, production of TLR proteins will be monitored by use of antibodies generated as part of the research. In addition, they will investigate the role of mannan as a regulator of expression of the co-stimulatory molecules B7-1 and B7-2, and of the proinflammatory cytokine TNF-alpha as these can be induced as a result of TLR-mediated signaling. They will determine whether whole cells and a variety of extracts of C. albicans and other yeast species invoke the same sort of immune response via interactions involving TLRs. Successful understanding of the interactions of pathogenic yeasts with TLRs should lay a foundation for development of immunological strategies that may augment defense responses in OPC and other infectious diseases.